Immunology

T- lymphocytes

T -lymphocytes

Originate from the BMS cells but emigrate to mature in the thymus, They play a central role in CMI.
Can be distinguished by the presence of special receptor on their cell surface called TCR.

Structure of the TCR complex

TCR - Complex

Cont,

T- Cell Receptor for Antigens (TCR):
The TCR are composed of 2 parts which are disulfide Linked Heterodimer (DSLH)
The TCR recognize the antigens in combination with MHC molecules


Cont,
1. DSLH : It is composed of 2 chains; alpha- chain and beta- chain .
These chains are located mainly extracellularly , with small intracellular portion. These chains are linked by disulfide bonds.
The alpha chain have 3 portions; variable ( V ) for specificity, Joining ( J ) and Constant ( C ), while beta- chain have V, Diversity ( D ), J, and C.
The combination of these segments give vast array of specificities. About 95-99 % of DSLH have alpha / beta chains. However, 1-5% have delta / gamma chains.

Cont,

2. CD3 :
Composed of 6 chains; 4 of them (1 delta,, 1 gamma and 2 epsilon) have half extracellularly and half intracellularly.
The other 2 chains are mainly intracellularly ( theta ).
The functions of CD3 is to support the DSLH and for transduction.

T cell subtypes and their functions

1.T – Helper cells
They express CD4 glycoprotein as monomere coreceptor on their surfaces to enhance signal transduction.
About 65% of total T cells.
To recognize exogenous Ags in association with MHC-class II on antigen presenting cells.
Can be subdivided into two subsets, TH1 and TH2.
TH1 secret cytokines that activate other T cells, NK cells & macrophages.

Cont,

TH1 cells Produce mainly IL-2 and INF-gamma and TNF- alpha
IL-2: Important for memory CD4 cells together with INF-gamma, and activate CD8 cytotoxic cells.
INF-gamma: Activates macrophages & increase their bactericidal activity.
T-H1 help B cells to produce IgG2, and IgM antibodies.
Th1 cells can be activated by INF-gamma, and IL-12.
Are critical for immunity to intracellular microorganisms, including obligate intracellular bacteria.


Cont,
TH2 secret cytokines that result in B cell activation.
1. Are critical for many extracellular pathogens including helminths.
2. Their activation is responsible for allergic inflammatory diseases and asthma.
3. Help B cells to produce IgG1 and IgE.
4. Produce IL-4, IL-5, IL-9, IL-10

T-Helper cell

T cell subtypes and their functions

2. Cytotoxic T cells
Represents about 35% of total T cells in blood & lymphoid tissues
Express CD8 glycoprotein heterodimere on their surfaces to strengthen the binding of T cells to APCs
Recognize their target by binding to Ag-associated MHC-class I.
Can destroy virally infected cells, tumor cells & also involved in transplant rejection

Cytotoxic T cells

Upon activation of Tc cells , they kill the target cell via two pathways. The 1st occurs when Tc cells release the cytotoxins perforin & granzymes. Perforin forms pores in the target cell's plasma membrane allowing granzymes to enter the target cell.
The 2nd pathway is via interactions of the surface protein FAS ligand on the Tc with the Fas molecule on the surface of the target cell. This interaction activate a series of cysteine proteases, the caspase cascade, that eventually lead to apoptosis.


Cytotoxic T cells

CD4 & CD8 cells

Types of T cells

3. Memory T cells
Persist for long-term after infection has resolved.
Quickly expand to large numbers of effector T cells when exposed to their cognate Ag.
Express the cell marker CD 45RO.

4. Regulatory T cells (T reg cell)

Formerly known as suppressor T cells.
Crucial for maintainace of immunological tolerance & suppression of auto-reactive T cells.
Major role is to shut down T cell –mediated immunity towards the end of an immune reaction.
They are CD4+ CD25+FoxP3+.

Types of T cells

5. γδ T cells
Small subset of T cell that possess a distinct T cell receptor on their surface.
Represent (1-5%) of total T cells & present in the human intestinal epithelial tissues.
Their TCR composed of one γ chain and one δ chain instead of α and β chains.
Their function is to recognize non-protein antigens.


Types of T cells
6. Natural killer T cells (NKT cells)

Natural Killer T (NKT) cells represent a distinct lineage of T cells that express an αβ T cell receptor (TCR) .
Share a number of cell surface markers in common with NK cells such as CD16, CD56
Express either CD4 or double negative, DN ( no CD4 or CD8).
These cells can perform functions of both CD4 (T helper) and CD8 (T cytotoxic) cells
Recognize Ag by a molecule called CD1d, once activated , they can produce cytokines & also release cytolytic cell killing molecules.
Able to recognize & eliminate tumor cells & virally- infected cells.

Development of T cells

T cells are derived from bone marrow stem cells.
Then migrate in the blood to the thymus.
T cell differentiation in the thymus is a complex multistep process.
The T lymphocytes in the thymus are called thymocytes.
Maturation starts in the cortex of the thymus & as thymocytes mature they go towards the medulla.
At every step of thymic maturation, from precursor to mature T cells, the developing T cells are in contact & interact with the nonlymphoid stromal cell of the thymus.

Development of T cells

The passage of T cells from the cortex to the medulla of the thymus is associated with development of ordered sequence of TCR re-arrangement similar to that of Ig .
If developing T cells fail to generate both chains of TCR (α & β), it dies by apoptosis.


Cont,
All the cortical thymocytes (T- cells) will be educated to recognize self from non-self antigens by contact with the HLA antigens (Class I & II) of the cortical stromal (non-lymphoid) cells.
In the thymus, the T cells which recognize self Ags proceed to full maturation , this is called positive selection. Other cells which do not recognize self Ags are selected out ( negative selection ) & die by apoptosis.

Cont,

The earliest thymocytes express neither CD4 nor CD8 & classed as double negative(DN ,no CD4 or CD8).
As they progress through their development, they become double positive (DP) ,CD4+CD8+.
Finally, they mature to single positive (SP) either CD4+ or CD8+ thymocytes that are released from the thymus to the blood as mature immunocompetent T cells.

T – cells maturation

Activation of T cells

1st signal is provided by binding of TCR with the peptide presented with MHC- II molecules on the surface of APC.
The 2nd signal is the interaction of co-stimulatory & adhesion pairs of molecules on the surface of APC and the T cell. The important adhesion molecules are:
CD40 on APC with CD40L on T cells.
B7 (CD80) on APC with CD 28 on T cells.
ICAM-1 on APC with LFA-1 on T cells.
LFA-3 on APC with CD2 on T cells.


T- cell activation